As natural products (NP) sales increase, the risk of adverse NP-drug interactions (NPDIs) increases, yet the pharmacokinetic (PK) elucidation and clinical relevance of putative NPDIs remain elusive. Assessing the risk of NPDIs is more challenging than that of drug-drug interactions (DDIs), often due to relatively scant PK knowledge of individual NP constituents that perpetrate these interactions. The proposed U54 Center will develop a roadmap for NPDI research through a series of well-designed human in vitro and in vivo studies (termed Interaction Projects) on 4-6 priority NPs that pose a potential risk for clinically relevant NPDIs. A repository will be developed for the data generated from the Interaction Projects, and results will be communicated to various target audiences through a public portal. This U54 Center is composed of an accomplished team of investigators, including pharmacokineticists with expertise in NPDIs, complemented by expertise in NP chemistry, DDIs, and health information communication. In collaboration with the Steering Committee, an innovative strategy that combines a mechanistic approach with practical considerations (e.g., popularity of the NPs) will be used to select and prioritize 4-6 NPs for further investigation in te Interaction Projects. Mechanistic aspects include curated clinical NDPI data from the widely used Drug Interaction Database (DIDB) of the Informatics Core, structural alerts, and compelling preliminary clinical and in silico NPDI data. Once selected, the NPs will be entered into a Decision Tree for assessment of NPDI liability and probable significance of interactions with victim drugs. In parallel, the Pharmacology Core will develop detailed Statements of Work for the human in vitro and in vivo studies - while the Analytical Core will source, acquire, and characterize the selected NPs - for the Interaction Projects. Upon completion of each project, the Analytical Core will analyze the PK samples, and the Pharmacology Core will develop physiologically-based PK models for further assessment of the clinical relevance of the Interaction Project results. Throughout these projects, the Informatics Core will create a data repository embedded within a public portal web-based application named, NaPDI app, for Natural Product-Drug Interaction application. The repository, built using the DIDB framework, will allow researchers to access both raw data and summarized results. The U54 Center will also develop and share Best Practices recommended for the conduct of NPDI studies, based on the experience with and results from the Interaction Projects, with the research communities via the public portal. Effective dissemination of the Interaction Project results will be ensured through user experience and brand content studies with target audiences - researchers/practitioners and lay public - to refine the public portal content. The Informatics Core will ensure that the U54 Center's results are archived, organized, analyzed, and well-publicized, allowing for improved design of future NPDI research and ultimately, improved decisions on the optimal management of clinically relevant NPDIs.